Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-06-25
2004-12-14
Shameem, Golam M M (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S365000, C548S202000, C548S204000, C556S437000, C549S214000
Reexamination Certificate
active
06831076
ABSTRACT:
The present invention relates generally to epothilon derivatives and to their use in the preparation of medicaments. The present invention relates especially to the preparation of epothilon derivatives of general formulae 1 to 7 shown hereinafter and to their use in the preparation of therapeutic compositions and compositions for plant protection.
In formulae 1 to 7 given above:
R═H, C
1
-
4
alkyl;
R
1
, R
2
, R
3
, R
4
, R
5
═H, C
1-6
alkyl,
C
1-6
acyl-benzoyl,
C
1-4
trialkylsilyl,
benzyl,
phenyl,
benzyl or phenyl each substituted by C
1-6
alkoxy,
C
6
alkyl, hydroxy or by halogen;
it also being possible for two of the radicals R
1
to R
5
to occur together to form a group —(CH
2
)
n
— wherein n is from 1 to 6, and the alkyl and acyl groups contained in the radicals are straight-chain or branched radicals;
Y and Z are either identical or different and each represents hydrogen, halogen, such as F, Cl, Br or I, pseudohalogen, such as —NCO, —NCS or —N
3
, OH, O—(C
1-5
)acyl, O—(C
1-6
)alkyl, O-benzoyl. Y and Z may also be the O atom of an epoxy group, epothilon A and B not being claimed, or one of the C—C bonds forms a C═C double bond.
In formula 3, X generally represents —C(O)—, —C(S)—, —S(O)—, —CR
1
R
2
—, wherein R
1
and R
2
are as defined above, or —SiR
2
— wherein R is as defined above.
In formula 4, X represents oxygen, NOR
3
, N—NR
4
R
5
or N—NHCONR
4
R
5
, wherein the radicals R
3
to R
5
are as defined above.
In formula 5, X represents hydrogen, C
1-18
alkyl, C
1-18
acyl, benzyl, benzoyl or cinnamoyl.
For epothilons A and B, see DE-A-41 38 042.
Compounds according to general formula 1 can be obtained starting from epothilon A and B and from their 3-O— and/or 7-O-protected derivatives by opening the 12,13-epoxy group. If hydrohalic acids are used for that purpose in a preferably non-aqueous solvent, there being obtained the halohydrins X═Hal, Y═OH and Y═OH, Y═Hal. Protonic acids, such as, for xample, toluenesulphonic acid and trifluoroacetic acid, result, in the presence of water, in 12,13-diols which are then acylated (e.g. with carboxylic acid anhydrides and pyridine or triethylamine/DMAP) or alkylated (alkylhalides and silver oxide) according to standard processes. For that purpose, the 3- and 7-hydroxy groups may be protected temporarily in the form of a formate (removal with NH
3
/MeOH) or of a p-methoxybenzyl ether (removal with DDQ).
Compounds according to general formula 2 are obtainable from epothilon A and B and also from their 3-O- and/or 7-O-protected derivatives by reduction, for example with NaBH
4
in methanol. If 3-OH and/or 7-OH are protected reversibly, then after acylation or alkylation and removal of the protecting groups there may be obtained 5-O-monosubstituted or 3,5- or 5,7-O-disubstituted derivatives of general formula 2.
Reactions of epothilon A and B with bifunctional electrophilic reagents, such as (thio)phosgene, (thio)carbonyldiimidazole, thionyl chloride or dialkylsilyl dichlorides or bistriflates yield compounds of general formula 3. Pyridine, trialkylamines, optionally together with DMAP or 2,6-lutidine in an aprotic solvent serve as auxiliary bases in the process. The 3,7-acetals of general formula 3 are produced by transacetalisation, for example of dimethylacetals in the presence of an acid catalyst.
Compounds according to general formula 4 are obtained from epothilon A and B or from 3-O- and/or 7-O—protected derivatives thereof by ozonolysis and reductive treatment, for example with dimethyl sulphide. The C-16-ketones may then be converted Into oximes, hydrazones or semicarbazones in accordance with standard processes known to the person skilled in the art. They are, moreover, converted into C-16-/C-17-olefins by Wittig, Wittig-Horner, Julia or Petersen olefination.
The 16-hydroxy derivatives according to general formula 5 are obtainable by reduction of the C-16-keto group, for example with an aluminium hydride or borohydride. If 3-OH and 7-OH are provided with suitable protecting groups, the 16-hydroxy derivatives may be either acylated or alkylated. The 3-OH and 7-OH groups are freed, for example, in the case of O-formyl by NH
3
/MeOH and, in the case of O-p-methoxybenzyl, by DDQ.
The compounds of general formula 6 are obtained from derivatives of epothilon A and B, in which the 7-OH group has been protected by acyl or ether groups, by, for example, formylating, mesylating or tosylating the 3-OH group and then eliminating it by treatment with a base, for example DBU. The 7-OH group can be freed as described above.
Compounds of general formula 7 are obtained from epothilon A and B or from 3-OH- and 7-OH-protected derivatives thereof by basic hydrolysis, for example with NaOH in MeOH or MeOH/water. Preferably compounds of general formula 7 are obtained from epothilon A or B or from 3-OH— or 7-OH-protected derivatives thereof by enzymatic hydrolysis, especially with esterases or lipases. The carboxy group can be converted to an ester with a diazoalkane after protection of the 19-OH group by alkylation.
Moreover, compounds of formula 7 may be converted into compounds of formula 1 by lactonisation in accordance with the methods of Yamaguchi (trichlorobenzoyl chloride/DMAP), Corey (aldrithiol/triphenylphosphine) or Kellogg (omega-bromic acid/caesium carbonate). Relevant working methods may be found in Inanaga et al. in Bull. Chem. Soc. Japan, 52 (1979) 1989; Corey & Nicolaou in J. Am. Chem. Soc., 96 (1974) 5614; and Kruizinga & Kellogg in J. Am. Chem. Soc., 103 (1981) 5183.
To prepare the compounds according to the invention, it is also possible to start from epothilon C or D, where, for the derivatisation, reference may be made to the derivatisation methods described above. The 12,13-double bond may be selectively hydrogenated, for example catalytically or with diimine; or epoxidised, for example with dimethyldioxirane or with a peracid; or converted Into a dihalide, dipseudohalide or diazide.
The invention relates also to compositions for plant protection in agriculture, forestry and/or horticulture, consisting of one or more of the above-mentioned epothilon derivatives or consisting of one or more of the above-mentioned epothilon derivatives together with one or more common carrier(s) and/or diluent(s).
Finally, the invention relates to therapeutic compositions consisting of one or more of the above-mentioned compounds or of one or more of the above-mentioned compounds together with one or more common carrier(s) and/or diluent(s). These compositions may especially demonstrate cytotoxic activities and/or cause immunosuppression and/or be used to combat malignant tumours; they are particularity preferred as cytostatic agents.
The invention is illustrated and described hereinafter in greater detail by the description of a number of selected embodiments.
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Hoefle Gerhard
Kiffe Michael
Gesellschaft fur Biotechnologische Forschung mbH (GBF)
Mathews, Collins Shepherd & McKay, P.A.
Shameem Golam M M
LandOfFree
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